Pancreas and islet transplantation are potential treatments for diabetes mellitus. Although controversial, considerable evidence supports the hypothesis that the microvascular lesions associated with diabetes mellitus are secondary to disordered metabolism and that complete correction of the metabolic defect would prevent their appearance or halt their progression. This concept provides a rationale for treatment. Our objective is to restore normal metabolism to insulin dependent diabetics who have demonstrated a propensity to develop the secondary complications of diabetes, using the best techniques currently available for pancreas or islet transplantation. The technical and immunological problems are not entirely solved, but considerable progress has been made during the past few years and with appropriate recipient and donor selection a high success rate should be possible. Four patients currently have functioning pancreas grafts. Diabetes has been obviated in three patients by islet autotransplantation after near total pancreatectomy for chronic pancreatitis, showing the technical feasibility of islet transplantation. We will apply these procedures to the following categories of patients: (1) Segmental pancreas allografts from cadaver or related donors to diabetic patients who have previously received renal allografts for treatment of end stage diabetic nephropathy and who therefore already require immunosuppression; (2) Segmental pancreas allografts from HLA identical normal donors to nonuremic diabetic patients who do not require a kidney transplant but with early, progressive neuropathy, retinopathy, or nephropathy; (3) Islet allografts in uremic diabetic patients simultaneous with cadaveric kidney transplants; from the same donor, (4) Islet autotransplants to patients who undergo pancreatectomy for treatment of chronic pancreatitis. Metabolic studies include 24 hour profiles for glucose and insulin (or C-peptide); glucose tolerance tests and urinary C-peptide excretion. Lesions of the eyes, nerve and kidneys, including biopsies of previously transplanted kidney, will be serially assessed. Initially, each patient will serve as their own control and regression of lesions will be highly significant. Ultimately, comparison must be made between diabetic patients treated with transplantation and those treated by conventional therapy.